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Stereoselective synthesis of certain trifluoromethyl-substituted alcohols

a trifluoromethyl and alcohol technology, applied in the field of selective synthesis of certain trifluoromethylsubstituted alcohols, can solve the problems of chiral hplc and other enantiomer separation methods, which are generally unsuitable for large-scale preparation of single enantiomer

Active Publication Date: 2005-10-20
BOEHRINGER INGELHEIM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024] In yet another aspect of the invention, the reduction of step (b) is accomplished using a reducing agent selected from lithium aluminum hydride (LAH), diisobutyl aluminum hydride (DIBAL), or a 65 wt. % solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-Al®), or using other conditions selected from trifluoroacetic acid anhydride/sodium iodide (P. Bravo et al., J. Org. Chem., 1992, 57, 2726), trifluoroacetic acid anhydride/2,4,6-trimethylpyridine (P. Bravo et al., J. Org Chem., 1990, 55, 4216), or hydrogen chloride in ethanol (J. L.

Problems solved by technology

Chiral HPLC and other enantiomer separation method, however, are generally unsuitable for large-scale preparation of a single enantiomer.

Method used

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  • Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
  • Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
  • Stereoselective synthesis of certain trifluoromethyl-substituted alcohols

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experimental examples

[0073] The invention provides processes for making compounds of Formula (X) or (X′). In all schemes, unless specified otherwise, R1 to R3 in the formulas below have the meanings of R1 to R3 in the Summary of the Invention section. For synthesis of intermediates, see the synthetic procedures disclosed in U.S. Patent Application Publication Nos. 2004 / 0023999 and 2004 / 0162321, which are each incorporated herein by reference in their entireties. Other intermediates used in the preparation of compounds of the invention are either commercially available or readily prepared by methods known to those skilled in the art.

[0074] The epoxide of Formula (II) is a key intermediate in the synthesis of certain racemic compounds of Formula (I), as described in U.S. Patent Application Publication No. 2004 / 0162321, which is hereby incorporated by reference. Treatment of the epoxide of Formula (II) with the nucleophile R5H, in the presence of base opens the epoxide to provide racemic (I) as shown belo...

example 1

Synthesis of (R)-2-[2-(5-Fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane

[0080]

[0081] To a suspension of (R)-(+)-methyl p-tolylsulfoxide (28.2 g, 183 mmol) in 200 mL of anhydrous THF at −78° C. was added lithium diisopropylamide (LDA) mono(tetrahydrofuran), 1.5 M solution in cyclohexane (122 mL, 183 mmol) over 30 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (46.3 g, 166 mmol) dissolved in 125 mL of THF was then added via cannula over 30 minutes. After 1.5 hours at −78° C., the reaction mixture was quenched with 600 mL of water and extracted first with a 600 mL portion of EtOAc and then a 400 mL portion of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate (NaHCO3) solution, washed with brine, dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (elut...

example 2

Synthesis of (R)-2-[2-(5-Fluoro-2-methylphenyl)-2-methylpropyl]-2-trifluoromethyloxirane

[0084]

[0085] To a suspension of (R)-(+)-methyl p-tolylsulfoxide (1.00 g, 6.48 mmol) in 10 mL of anhydrous THF at −78° C. was added LDA mono(tetrahydrofuran), 1.5 M solution in cyclohexane (4.32 mL, 6.48 mmol) over 5 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (1.55 g, 5.90 mmol) was then added via cannula with the aid of 4 mL of THF over 5 minutes. After 1 hour at −78° C., the reaction mixture was quenched with 50 mL of water and extracted with three 50 mL portions of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 15%-25% EtOAc / hexanes) afforded sequentially (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylpheny...

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Abstract

A process for stereoselective synthesis of a compound of Formula (X) or Formula (X′) wherein R1, R2, and R3 are as defined herein, the process comprising: (a) reacting the starting material of formula A with a chiral sulfoxide anion source in a suitable solvent to prepare a compound of formula C or C′; (b) reducing the sulfoxide of formula C or C′ in a suitable solvent to obtain the compound of formula D or D1; and (c) cyclizing the compound of formula D or D′ in a suitable solvent to form the epoxide compound of Formula (X) or Formula (X′), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

Description

RELATED APPLICATIONS [0001] This application claims benefit of U.S. Ser. No. 60 / 557,597, filed Mar. 30, 2004, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to the stereoselective synthesis of certain trifluoromethyl-substituted alcohols. BACKGROUND OF THE INVENTION [0003] Trifluoromethyl-substituted alcohols of formula (I) have been described as ligands that bind to the glucocorticoid receptor. These compounds are potential therapeutics in treating a number of diseases modulated by glucocorticoid receptor function, including inflammatory, autoimmune and allergic disorders. Examples of these compounds are described in U.S. Patent Application Publication Nos. 2003 / 0232823, 2004 / 0029932, and 2004 / 0023999, which are each incorporated herein by reference in their entireties and are hereinafter termed “the Trifluoromethyl-Substituted Alcohol Patent Applications”. [0004] It is well known in the art that enantiomers of...

Claims

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Application Information

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IPC IPC(8): C07D301/02C07D303/08C07D303/22C07D407/06
CPCC07D301/02C07D407/06C07D303/22C07D303/08
Inventor LEE, THOMAS WAI-HOPROUDFOOT, JOHN ROBERT
Owner BOEHRINGER INGELHEIM PHARMA INC
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